Hakky sobotka



Patented June 7, 1932 'UNI'I'ED STATES PATENT OFFICE HARRY SOBOTKEA, OF NEW YORK, N. Y.

DEXTRQ-PHENYL-5-ETHYL HYDANTOIN No Drawing. Application filed September 8, 1930. Serial No. 480,617.

My invention relates to an improvement employing the resolution of optically acin hypnotics of the hydantoin group, consisttive compounds and yielding satisfactory ing in an increase of their beneficial, soporifamounts of optically active doubly suberous, sedative, hypnotic and narcotic action stituted hydantoins in a theoretical yield, in

5 with simultaneous elimination of their insome instances. 55

jurious toxic properties. Example l.20.2 grams optically inactive Doubly substituted hydantoins of the Forphenyl-ethyl-hydantoin were dissolved in 200 mula I are known for their sedative, hypcc. absolute alcohol, and a filtered solution notic and narcotic effects. of 46.6 grams brucin alkaloid in 200 cc. ab-' R1 (JO-NH solute alcohol was added. About 32 grams (1) c I V of crystals consisting of the brucin salt of 2 Nil-00 dextro-phenyl-ethylhydantoin, appeared on Emil Fischer and Mehring observed the 9, 111 the I h ti ti f di th l h d t i These crystals were redissolved in absolute 15 (1{ =R =OH GH i 1902 ph lalcohol and 100 cc. N/l sulfurlc acid was ethylhydantoin is used as a sedative in epilepadded- The solutloil Was dlhlted Wlth Water ti d h i Ph 1 1 d to a final al cohol content of about 10 percent. phenyl-isobutylhydantoins are said to show The p p f of crystanme yl" i il efiects However, 11 th 11 ethyl-hydantoin was filtered, drled and purl- 20 stances show ill after-effects besides their fled y Several crystallizations from dilute pharl'nacglogical purpose. They are kn n ethyl-alcohol until the reaction 01 the alkato have caused severe damage, and 1016. became negative. The pure substance other toxic reactions in several cases, and a meltlng P 0f they cause drug eruption accompanied by Whlle the I ph ylthyl-hydant m 95 high temperatures in the majority of the melts $51990- Its Optlcal actlvlty 15 patients, especially in children. o o I found that these hydantoins when sub- (00D +118 to +123 stituted with two groups difierent from each depindmg on nature of the Solvent conce other, e. g. two of the following, methyl, tratlon and temperature ethyl, propyl and other aliphatic groups The mother liquor of the brucin-dextroaromatic groups as phenyl, hydroaromatic phenyl'ettlyl'hydantom Salt was acldlfied and groups as cyclohexyl, and substituted derivdlluted Wlth Water to 10 Percent alcohol P atives of the aforementioned groups viz. tenth free P n lt i bromo-allyl, may be separated by certain was Obtamed as a wtnt'e.cry.staume t 35 procedures into two Optically active forms tate; upon ISCIYSttLlllZatlOl'l it has a melting rotating the plane of polarized light to the P of 235 and an Optlcal rotatlon of same degree to the right and to the left side a -12 respectively, and that these optical antipodes Y may also be obtained separately by similar chemical procedures. As hydantoins react as acids, they can be resolved into their optically active moieties through salt formation with optically active bases, particularly alkaloids. The optically active substances thus obtained not only differ from the optically inactive hydantoin by their optical ac- C H 000E tivity, but also by a completely new set of (II) 6 o properties, viz. by their melting points, solubility in various solvents etc. Below are plus the double amount of urea is dissolved given examples to illustrate various methods in 25 cc. of water and heated for 10 hours The brucin was recovered from both halves in satisfactory quantity.

Both forms may also be obtained separately by applying the syntheses for disubstituted hydantoins to optically active amino acids or related derivatives.

Example I I .5 grams optically active 5 phenyl-ethyl-amino-acetic acid (II) with reflux. The excess urea is removed by fractional crystallization from water and dilute alcohol. Both the deXtraand levo-rotatory forms of phenyl-ethyl-hydantoic acid (III) c0115 coon may be obtained from the respective phenylethyl-glycine =phenyl-ethyl-amino-acetic acid). Instead of urea alkali cya-nate may be employed. A concentrated solution of either deXtroor levo-phenyl-ethyl-hydantoic acid upon heating with dilute acid, e. gsulfuric acid, is converted into the corresponding optically active phenyl-ethyl-hydantein. A satisfactory yield of either substance was obtained showing melting point, optical rotation and biological properties identical with the substances obtained according to EX- ample I.

Example lI[.-Optically active disubstituted amino-acetic acid may be readily converted into its amide (IV) which upon treatment with chemically active substances containing a CO group as phosgene, chloro-carbonic ester, diphenylcarbonate will form a hydantoin-ring retaining the optically active configuration on the doubly substituted carbon atom.

Example IV.Optically active disubstituted amino-aceto-nitril (V) R1\ GEN (V) Rz NHQ or an ester of disubstituted amino-acetic acid as its ethyl ester (VI) I R1\ COOC2H5 (VI) R: NHz when treated with alkali cyanate or urea will yield the nitril or ester of the disubstituted optically active hydantoic acid respectively, which in turn, may be converted by saponification with acid, e. g. sulfuric acid, into the corresponding disubstituted optically active hydantoin.

Example V.-The action of alkali hypo halite upon optically active disubstituted cyanoacetamides (VII) R1 C ON Hz .0 R2 GEN results in the formation of the corresponding optically active hydantoin through an oxidative rearrangement of the CN group.

(R R C('CONH )NGO) It is remarkable that these syntheses can be applied without appreciable concomitant racemization; this stability is due to the absence of a hydrogen atom on the optically active carbon atom.

Besides the separation of the dextroand levo-form of these disubstituted hydantoins and their parent substances by purely che1nical procedures, biological means for their resolution are furnished by microorganisms and enzymes, I found it possible to grow certain moulds like aspergillus on an aqueous solution of pure optically inactive phenylethyl-hydantoin-sodium. Since the mould in this instance preferred the levo-iorm a nutrient, the solution after 2 days was dextrorotatory and deXtro phenyl ethyl hydantoin could be isolated from it in crystalline form.

Biological properties of optical antipodes of disubstituted hydantoins.

Patients given the levorotatory substance, in several instances developed a drug eruption with the same features those observed upon administration of the optically inactive drug. The rash appears during the second week after the first dose starting from the extremities, measle-like in appearance and accompanied by raised body temperature.

The other form, in the case of phenylethyl-hydantoin, the deXtro-rotatory form, is as strong a hypnotic and sedative as the optically inactive drug, both on humans and cn'animzals, independent of the route of administration. In rare cases has this pharmacologically effective substance produced a drug eruption or concomitant untoward reactions. These injurious reactions as observed with the race-mic mixture are mainly due to the pharm-acologically ineffective antipode. In mixtures containing unequal amounts of the dcxtroand levo-form the )harmacological effect was found proportional to the share of the deXtro-it'orm' preseat, the undesirable eilects depending on the amount of the levo-antipode present.

I claim,

A dextro-rotatory substance of the formula can OO-NH CzHa NH-OO HARRY SOB'OTKA.

IZD 

